{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T20:37:14Z","timestamp":1787690234453,"version":"build-2784847793"},"reference-count":109,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,10,25]]},"abstract":"<jats:p>This paper suggests a chemical mechanism for the earliest stages of Alzheimer\u2019s disease (AD). Cerebrospinal fluid (CSF) flow stresses provide the energy needed to induce molecular conformation changes leading to AD by initiating amyloid-\u03b2 (A\u03b2) and tau aggregation. Shear and extensional flow stresses initiate aggregation in the laboratory and in natural biophysical processes. Energy-rich CSF flow regions are mainly found in lower brain regions. MRI studies reveal flow stress \u201chot spots\u201d in basal cisterns and brain ventricles that have chaotic flow properties that can distort molecules such as A\u03b2 and tau trapped in these regions into unusual conformations. Such fluid disturbance is surrounded by tissue deformation. There is strong mapping overlap between the locations of these hot spots and of early-stage AD pathology. Our mechanism creates pure and mixed protein dimers, followed by tissue surface adsorption, and long-term tissue agitation ultimately inducing chemical reactions forming more stable, toxic oligomer seeds that initiate AD. It is proposed that different flow stress energies and flow types in different basal brain regions produce different neurotoxic aggregates. Proliferating artery hardening is responsible for enhanced heart systolic pulses that drive energetic CSF pulses, whose critical maximum systolic pulse energy location migrates further from the heart with increasing vascular disease. Two glymphatic systems, carotid and basilar, are suggested to contain the earliest A\u03b2 and tau AD disease pathologies. A key to the proposed AD mechanism is a comparison of early chronic traumatic encephalopathy and AD pathologies. Experiments that test the proposed mechanism are needed.<\/jats:p>","DOI":"10.3233\/jad-220622","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T14:20:37Z","timestamp":1663683637000},"page":"33-59","source":"Crossref","is-referenced-by-count":7,"title":["An Alzheimer\u2019s Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease"],"prefix":"10.1177","volume":"90","author":[{"given":"Conrad N.","family":"Trumbore","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Raghunandan","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University of Rochester, Rochester, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-220622_ref1","first-page":"5380346","article-title":"Clinical trials in Alzheimer\u2019s disease: A hurdle in the path of remedy","volume":"2020","author":"Oxford","year":"2020","journal-title":"Int J Alzheimers Dis"},{"key":"10.3233\/JAD-220622_ref2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/NRL.0000000000000320","article-title":"Alzheimer disease clinical trials targeting amyloid: Lessons learned from success in mice and failure in humans","volume":"26","author":"Reiss","year":"2021","journal-title":"Neurologist"},{"key":"10.3233\/JAD-220622_ref3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2176\/nmc.oa.2019-0170","article-title":"Simple identification of cerebrospinal fluid turbulent motion using a dynamic improved motionsensitized driven-equilibrium steady-state free precession method applied to various types of cerebrospinal fluid motion disturbance","volume":"60","author":"Atsumi","year":"2020","journal-title":"Neurol Med Chir (Tokyo)"},{"key":"10.3233\/JAD-220622_ref4","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1073\/pnas.1702724114","article-title":"Inducing protein aggregation by extensional flow","volume":"114","author":"Dobson","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-220622_ref5","doi-asserted-by":"crossref","first-page":"979","DOI":"10.3233\/JAD-201025","article-title":"Shear-induced amyloid aggregation in the brain: V. 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